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Long-term follow-up of givosiran treatment in patients with acute intermittent porphyria from a phase 1/2, 48-month open-label extension study

Publication Details

Orphanet Journal of Rare Diseases

October 2024

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Author(s)

Eliane Sardh¹, Manisha Balwani², David C Rees³, Karl E Anderson⁴, Gang Jia⁵, Marianne T Sweetser⁶, Bruce Wang⁷

Affiliations

¹CMMS - Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Karolinska Institutet, Solna, 171 64, Stockholm, Sweden; ²Department of Genetics and Genomic Sciences, Icahn School of Medicine, New York, NY, USA; ³Comprehensive Cancer Centre, King's College Hospital, London, UK; ⁴Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Texas Medical Branch, Galveston, TX, USA; ⁵Medical Affairs Statistics, Alnylam Pharmaceuticals, Cambridge, MA, USA; ⁶Clinical Development, Alnylam Pharmaceuticals, Cambridge, MA, USA; ⁷Department of Medicine and UCSF Liver Center, University of California San Francisco, San Francisco, CA, USA

Abstract

Background:

Acute hepatic porphyria is a group of multisystem disorders of which acute intermittent porphyria is the most common subtype. Givosiran, a subcutaneously administered RNA interference therapeutic targeting liver ALAS mRNA, is approved for treating these disorders. This Phase 1/2 open-label extension study (NCT02949830) evaluated the long-term safety and efficacy of givosiran in adults with acute intermittent porphyria, with follow-up of up to 48 months, which is the longest follow-up of givosiran treatment to date. Participants were adults aged 18–65 years who completed part C of the Phase 1 givosiran study (NCT2452372).

Methods:

Enrollees received givosiran for up to 48 months. Primary and secondary endpoints included the incidence of adverse events, changes in urinary delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) levels, annualized rate of porphyria attacks, and annualized hemin use. Quality of life was assessed using the EQ-5D-5L instrument as an exploratory endpoint.

Results:

Sixteen patients (median age: 39.5 years) participated. Common adverse events included abdominal pain, nasopharyngitis, and nausea (50% each), with injection-site erythema (38%) and injection-site pruritus (25%) noted as frequent treatment-related reactions. Givosiran therapy reduced annualized rates of porphyria attacks and hemin use by 97% and 96%, respectively. From months > 33 to 48, all patients were free from attacks requiring significant medical intervention and did not use hemin. There were substantial reductions in median urinary ALA and PBG of 95% and 98%, respectively. Additionally, a clinically meaningful improvement in quality of life was observed.

Conclusions:

In the longest follow-up of givosiran-treated patients reported to date, the therapy maintained an acceptable safety profile and demonstrated sustained improvements in clinical outcomes over 4 years in patients with acute intermittent porphyria.